WO1996038417A1

WO1996038417A1 - N-oxides as antibacterial agents

Info

Publication number: WO1996038417A1
Application number: PCT/EP1996/002171
Authority: WO
Inventors: Hubert Rast; Martin Scheer; Werner Hallenbach
Original assignee: Bayer Aktiengesellschaft
Priority date: 1995-05-31
Filing date: 1996-05-20
Publication date: 1996-12-05
Also published as: BR9608593A; CA2222552A1; ATE204256T1; PL187322B1; AR034452A2; PL323622A1; NO319510B1; SK283994B6; EP0828715B1; ZA964414B; AU5900596A; DE19519822A1; CA2222552C; KR19990022044A; HUP9802076A2; CN1190958A; HUP9802076A3; AU707628B2; US6114351A; DE59607503D1

Abstract

The present invention relates to novel antibacterial agents, especially orally administrable agents, based on N-oxides of saturated nitrogen-containing heterocycles substituted by quinolone carboxylic acids or naphthyridone carboxylic acids, and novel active agents and their production.

Description

N-OXIDES AS AN ANTIBACTERIAL AGENT

The present invention relates to new antibacterial agents, in particular orally administrable agents, based on N-oxides of saturated nitrogen-containing heterocycles which are substituted by quinolonecarboxylic acids or naphthyridonecarboxylic acids, and to new active compounds and their preparation.

N-oxides of saturated nitrogen-containing heterocycles which are substituted by quinolone carboxylic acids are known as metabolites of the active substances on which they are based. However, it is also known that these metabolites have no antibacterial activity (J. Guibert et. Al. Pathol. Biol. 1989, 37 (5), 406-10; Venezia et. Al. Antimicrob. Agents. Chemot. 1989, 33 (5), 762-6).

It has also been known that oral administration of quinolonic or naphthyridonecarboxylic acid based antibacterial agents via animal feed or drinking water is often problematic. Drinking water or feed are often refused and the medication dosage is insufficient. Since the medication via the feed or the drinking water is a very simple and stress-free mode of administration for the veterinarian, animal owner and animal to be treated, there is a high need for agents to be administered orally. It is desirable to use the highly effective quinolonecarboxylic acid series antibacterial agents such as e.g. To be able to reliably administer enrofloxacin via the feed.

It was found:

1. Antibacterial agents based on N-oxides of saturated nitrogen-containing heterocycles which are substituted by quinolone or naphthyridonecarboxylic acids of the formula (I) or (II)

in which

X represents hydrogen, halogen, C _M alkyl, C _M alkoxy, NH ₂ ,

Y for structural remains

stands in what

R ⁴ represents straight-chain or branched C ₁ -C ₄ -alkyl, cyclopropyl, acyl with 1 to 3 C atoms optionally substituted by hydroxy or methoxy,

R represents hydrogen, methyl, phenyl, thienyl or pyridyl,

R ^{6 is} hydrogen or C ₁ . ₄ alkyl,

R ^{7 is} hydrogen or C _j . ₄ alkyl,

R 8 ^{8 represents} hydrogen or C _M alkyl, and

R ^{1 represents} an alkyl radical with 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl, 2,4-difluorophenyl or methylamino, R represents hydrogen or alkyl with 1 to 6 carbon atoms which is optionally substituted by methoxy or 2-methoxyethoxy, and cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl,

R represents hydrogen, methyl or ethyl and

A stands for nitrogen or = CH-, = C (halogen) -, = C (OCH ₃ ) - = C (CH ₃ ) -,

B represents oxygen, optionally substituted by methyl or phenyl = N- and = CH ₂ ,

Z stands for = CH- or = N-,

and their pharmaceutically usable hydrates, acid addition salts and salts with bases. The compounds of the formulas I and II can be present in the form of their racemates or in enantiomeric forms.

2. Agents based on animal feed or drinking water

N-oxides of saturated nitrogen-containing heterocycles which are substituted by quinolone or naphthyridonecarboxylic acids of the formulas (I) or (II)

in which

Z and X have the meaning given above,

Y for structural remains

stands in what

R .5 represents hydrogen, methyl, phenyl, thienyl or pyridyl,

R> 6 ° represents hydrogen or C ^ alkyl,

R ^{7 represents} hydrogen or C _M alkyl,

R ^{8 represents} hydrogen or C ^ alkyl, and

R ^{1 represents} an alkyl radical with 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl, 2,4-difluorophenyl or methylamino, R ^{2 represents} hydrogen or alkyl with 1 to 6 carbon atoms which is optionally substituted by methoxy or 2-methoxyethoxy and cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl,

R ^{3 represents} hydrogen, methyl or ethyl and

A stands for nitrogen or = CH-, = C (halogen) -, = C (CH ₃ ) -, = C (OCH ₃ ),

B represents oxygen, optionally = CH ₂ substituted by methyl or phenyl,

and their pharmaceutically usable hydrates, acid addition salts and

Salts with bases.

3. New N-oxides of saturated nitrogen-containing heterocycles which are substituted by quinone carboxylic acids of the formula (Ia)

in which

Y for structural remains

stands in what R ⁴ substitu¬ iertes optionally substituted by hydroxy or methoxy chain or branched C _j -C ₄ - alkyl, Cyclo¬ propyl, acyl having 1 to 3 carbon atoms,

R ^{5 represents} hydrogen, methyl, phenyl, thienyl or pyridyl,

R ^{6 represents} hydrogen or C _M alkyl,

R ^{7 represents} hydrogen or C _M - alkyl,

R ^{8 represents} hydrogen or C _M alkyl, and

R represents hydrogen or optionally methoxy-substituted alkyl having 1 to 4 carbon atoms and benzyl, 2-oxopropyl,

Phenacyl and ethoxycarbonylmethyl,

A stands for = N-, = CH-, = C (halogen) - or = C (OCH ₃ ) -,

as well as their pharmaceutically usable hydrates or acid addition salts or salts with bases.

It has also been found that the compounds of the formula (Ia) are obtained when

a) the corresponding compounds (III)

in which

Y 'represents the saturated nitrogen-containing heterocycle on which the N-oxide radicals Z are based, A and R ^{1 have} the meaning given above,

reacted with oxygen-releasing agents,

or if you

b) compounds of the formula (IV)

in which

Z, A, R ¹ , R ^{2 have} the meaning given above and

X is halogen, preferably fluorine or chlorine,

nitrogen-containing heterocycles of the formula (V) saturated with N-oxides

Y - H (V)

in which

Y has the meaning given above,

if appropriate in the presence of acid binders.

Compounds of the formula (I) are preferred

in which

A stands for = CH-,

R ¹ is propyl optionally substituted by halogen C _j -C ₃ alkyl or Cyclo¬, R ^{2 represents} hydrogen or C alkyl,

Y for structural remains

stands in what

R ⁴ represents optionally substituted by hydroxy straight or branched C _j -C ₃ alkyl, oxalkyl having 1 to 4 C atoms,

R ^{5 represents} hydrogen, methyl or phenyl,

R ^{7 represents} hydrogen or methyl,

and their pharmaceutically usable hydrates and acid addition salts and their alkali, alkaline earth, silver and guanidinium salts.

Compounds of the formula (I) are particularly preferred

in which

A stands for = CH-,

R ^{1 represents} cyclopropyl,

R ^{2 represents} hydrogen, methyl or ethyl,

Y for structural remains

stands in what

R represents methyl, ethyl optionally substituted by hydroxy,

R ^{5 represents} hydrogen or methyl,

R ^{7 represents} hydrogen or methyl,

and their pharmaceutically usable hydrates and acid addition salts as well as the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids.

The N-oxides of the active compounds with the common names enrofloxacin, danofloxacin, ofloxacin, norfloxacin, benofloxacin, sarafloxacin, difloxacin, orbifloxacin, marbofloxacin are particularly preferred.

The N-oxides of the active substances enrofloxacin, marbofloxacin and ofloxacin may be mentioned in particular.

According to method a), 1-cyclopropyl-7- (4-ethyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is used to prepare the new N-oxides and

Hydrogen peroxide as starting materials, the course of the reaction can be represented by the following formula:

If, for example, 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester and 1- Ethylpiperazine-N-oxide as starting materials, the course of the reaction can be represented by the following formula:

The quinolone carboxylic acids or esters of the formulas (III) and (IV) used as starting materials according to methods a) and b) are known or can be prepared by known processes.

Examples include: l-ethyl-6-fluoro-l, 4-dihydro-4-oxo-7- (4-ethyl-l-piperazinyl) -quinoline-3-carboxylic acid, l-ethyl-6-fluoro-l , 4-dihydro-7- (4-methyl-l-piperazinyl) -4-oxo-quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- ( 4-ethyl-1-piperazinyl) - 1, 8-naphthyridine-

3-carboxylic acid, 9-fluoro-3-methyl-10- (4-methyl-l-piperazinyl) -7-oxo-2,3-dihydro-7,4-pyrido [1, 2,3-di] - 1 , 4-benzoxazin-6-carboxylic acid, 9-fluoro-5-methyl-8- (4-methyl-1-piperazinyl) -6,7-dihydro-l-oxo-1H, 5H-benzo [ij] quinolicin-2 -carboxylic acid, 6-fluoro-1 - (4-fluorophenyl) - 1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid, 6-fluoro-1 - (2-fluoroethyl) - 1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid, l-ethyl-6,8-difluoro-1,4 dihydro-4-oxo-7- (4-methyl-l-piperazin-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- ( 4-ethyl-1-piperazinyl) -quinoline-3-carboxylic acid, 1-cyclopropyl -6-fluoro-l, 4-dihy dro-4-oxo-7- (4-ethyl-l-piperazinyl) -quinolin-3- ethyl carboxylate, l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid, 1-cyclopropyl-8-chloro -6-fluoro-l, 4-dihydro-4-oxo-7- (4-methyl-l-piperazinyl) -quinoline-3-carboxylic acid, 1-cyclo-propyl-8-chloro-6-fluoro- 1, 4-dihy dro-4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid, 7-chloro-l-ethyl-6-fluoro-l, 4-dihydro-4-oxo-quinoline- 3-carabonic acid ethyl ester, l-ethyl-6,7-difluoro-l, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 7-chloro-1-ethyl-6-fluoro-1, 4-dihy dro -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7,4-pyrido [1,2,3-de] - l, 4-benzoxacin-6-carboxylic acid ethyl ester, 8,9-difluoro-5-methyl-6,7-dihydro-l-oxo-lH, 5H-benzo [i, j] quinolicin-2-carboxylic acid ethyl ester, 7-chloro 6-fluoro-l- (4-fluorophenyl) -l, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 6,7,8-trifluoro-l- (4-fluorophenyl) - 1, 4- dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 7-chloro-1-cyclo- propyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 7-chloro-1-cyclo-propyl-6-fluoro-l, 4-dihydro-4-oxo-quinoline-3 -carboxylic acid methyl ester, 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid-n-butyl ester, 1-cyclopropyl-6,7-difluoro-1, 4 -dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 1-cyclopropyl-6,7,8-trifiuor-l, 4-dihydro-4-oxo-quinoline-3-carabonic acid ethyl ester, 8-chloro-l-cyclopropyl -6,7-difluoro-l, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 1-cyclopropyl-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-l, 8-naphthyridine -3-carboxylic acid ethyl ester.

The amines of the formula (III) used as starting compounds are known. Chiral amines can be used both as racemates and as enantiomerically or diastereomerically pure compounds.

Further examples are:

1-methylpiperazine,

1-ethylpiperazine, N (2-hydroxyethyl) piperazine,

N (2-methoxyethyl) piperazine,

1-cyclopropylpiperazine,

1 -phenylpiperazine,

1,2-dimethylpiperazine, 2,5-diazabicyclo [2.2.1] heptane,

2-methyl-2,5-diazabicyclo [2.2.1] heptane,

2,5-diazabicyclo [2.2.2] octane,

2-methyl-2,5-diazabicyclo [2.2.2] octane,

1,4-diazabicyclo [3.2.1] octane.

In the reaction of the compounds of formula (III) with oxygen

The compounds (III) as such or in the form of their salts, e.g. Mesylates used.

The following oxygen-releasing agents may be mentioned in detail:

Hydrogen peroxide, oxygen, organo-hydroperoxides such as tert. Butyl hydroperoxide, cumene hydroperoxide. The addition of a metal catalyst can be favorable (Mo, V, Ti). Peracids: such as performic acid, peracetic acid, perbenzoic acid, monoperphthalic acid, sulfomonoperic acid.

Peroxides such as Benzoyl peroxide, perborate, percarbonate.

ozone

The reaction temperatures can be varied over a wide range. Generally one works between -20 ° C and 200 ° C, preferably between 20 ° C and 150 ° C.

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.

The reaction is preferably carried out in a diluent.

All inert organic solvents are used as diluents. These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, and furthermore ethers such as diethyl - And dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, nitriles, such as Acetonitrile and propionitrile, benzonitrile, glutaric acid dinitrile, and also amides, such as e.g. Dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as tetramethylene sulfone and hexamethylphosphoric acid triamide, furthermore alcohols such as methanol, ethanol, n- and i-propanol, glycol monomethyl ether and water. Mixtures of these diluents can also be used.

The reaction can be carried out in the presence of auxiliary bases such as e.g. Alkali and alkaline earth hydroxides (Li, Na, K, Mg, Ca), alkali and alkaline earth carbonates and

Hydrogen carbonates (Li, Na, K,) phosphates, salts of organic acid such as Na acetate can be carried out. When carrying out the process according to the invention, 1 to 15 mol, preferably 1 to 6 mol, of the oxygen-donating agent are employed per mol of compound (III).

The reaction mixture is worked up in a manner known per se. If peracids are used as the oxidizing agent, the corresponding acid addition salts of the compounds (I) and (II) can be obtained directly:

e.g. Enrofloxacin + peracetic acid -> Enrofloxacin-N-oxide acetate.

The acid addition salts of the compounds according to the invention are prepared in a customary manner, for example by dissolving the betaine in a sufficient amount of aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile. You can also heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monoethyl ether and then evaporate to dryness or vacuum the precipitated salt. Examples of pharmaceutically usable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid,

Lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. Furthermore, the compounds according to the invention can be bound to acidic or basic ion exchangers.

The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in a deficient alkali metal or alkaline earth metal solution, filtering undissolved betaine and evaporating the filtrate to dryness. Sodium, potassium or calcium salts are pharmaceutically suitable. The corresponding silver salts are obtained by reacting an alkali or alkaline earth salt with a suitable silver salt such as silver nitrate.

The agents according to the invention or the compounds on which they are based have a strong antibiotic effect and, with low toxicity, show a broad antibacterial spectrum against gram-positive and gram-negative germs, in particular also against those which are resistant to various antibiotics, such as penicillins and cephalosporins. Aminoglycosides, sulfonamides, tetracyclines. These valuable properties enable their use as chemotherapeutic agents in medicine and veterinary medicine and as substances for the preservation of inorganic and organic materials, in particular of all kinds of organic materials, for example polymers, lubricants, paints, fibers, leather, paper and wood , of food and water.

The compounds according to the invention are active against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacterial-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.

With favorable warm-blooded toxicity, the active substances are particularly suitable for combating bacterial diseases which occur in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development as well as against resistant and normally sensitive strains. By combating bacterial diseases, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry.

Livestock and breeding animals include mammals such as Cattle, horses, sheep,

Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, pigeons, bird species for home and zoo keeping. It also includes farm and ornamental fish.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

The fish include utility, breeding, aquarium and ornamental fish of all ages that live in fresh and salt water. The useful and farmed fish include z. B. carp, eel, trout, white fish, salmon, bream, roach, rudd, chub,

Sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthread seabream (Spams auratus), Tilapia spp., Chichliden species such as B. Plagioscion, Channel catfish. The agents according to the invention are particularly suitable for the treatment of fish fry, e.g. B. Carp with a body length of 2-4 cm. The agents are also very suitable for eel fattening.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or, preferably, enterally in the form of suitable preparations.

The enteral application of the active ingredients takes place e.g. orally in the form of powder, suppositories, tablets, capsules, pastes, drinkers, granules, drenches, boluses, medicated feed or drinking water.

Suitable preparations are:

Solutions such as oral solutions, concentrates for oral administration after dilution;

Emulsions and suspensions for oral semi-solid preparations;

Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules.

Solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. The solutions are filtered and filled.

The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.

The active ingredients can optionally also be dissolved in physiologically compatible vegetable or synthetic oils. The following may be mentioned as solubilizers: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration.

Dyes are all dyes approved for use on animals, which can be dissolved or suspended.

Absorbing substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. Substances from the class of benzophenones or novantisol acid.

Oral emulsions are either water in oil or oil in water.

They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and with the aid of suitable emulsifiers and, if appropriate, other auxiliaries such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers and viscosity-increasing substances homogenized the solvent of the other phase.

The following may be mentioned as the hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as

Caprylic / capric acid bigylceride, triglyceride mixture with vegetable fatty acids of chain length C _8.12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of C ₈ / C _{] 0} fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C _{] 6} -C ₁₈ , isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol esters of saturated fatty acids the chain length C ₁₂ -C ₁₈ , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as dibutyl phthalate, diisopropyl adipate, the latter related ester mixtures including fatty alcohols such as isotridecyl alcohol, 2-octyl alcohol, 2-octyl alcohol dodecyl alcohol.

Fatty acids such as Oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase:

Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;

ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;

anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;

cationic surfactants such as cetyltrimethylammonium chloride.

The following may be mentioned as further auxiliaries: substances which increase the viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols , Waxes, colloidal silica or mixtures of the listed substances.

Suspensions are prepared by adding the active ingredient in a carrier liquid, optionally with the addition of other auxiliary substances such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers suspended.

All homogeneous solvents and solvent mixtures are mentioned as carrier liquids.

The surfactants specified above may be mentioned as wetting agents (dispersants).

Further additives mentioned are those mentioned above.

Semi-solid preparations differ from the suspensions and emulsions described above only in their higher viscosity.

To prepare solid preparations, the active ingredient is mixed with suitable excipients, if appropriate with the addition of auxiliaries, and brought into the desired form.

All physiologically compatible solid inert substances may be mentioned as carriers. All of these serve inorganic and organic substances. Inorganic substances are e.g. Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

Organic substances are e.g. Sugar, cellulose, food and feed such as milk powder, animal meal, cereal flour and meal, starches.

Excipients are preservatives, antioxidants, dyes, which have already been listed above.

Other suitable auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline

Cellulose. The active substances can also be present in the preparations as a mixture with synergists or with other active substances.

Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm to 20 percent by weight, preferably 0.1 to 10 percent by weight.

Preparations that are diluted before use contain the active ingredient in

Concentrations from 0.5 to 90 percent by weight, preferably from 1 to 50 percent by weight.

In general, it has proven to be advantageous to administer amounts of about 0.5 to about 50 mg, preferably 1 to 20 mg, of active ingredient per kg of body weight per day in order to achieve effective results.

The active ingredients can also be administered together with the animal's feed or drinking water.

Feed and food contain 0.01 to 100 ppm, preferably 0.5 to 50 ppm of the active ingredient in combination with a suitable edible material.

Such feed and food can be used for medicinal purposes as well as for prophylactic purposes.

Such feed or food is produced by mixing a concentrate or a premix containing 0.5 to 30%, preferably 1 to 20% by weight of an active ingredient in admixture with an edible organic or inorganic carrier with conventional feed. Edible carriers are e.g. Corn meal or corn and soybean meal or mineral salts, which preferably contain a small amount of an edible dust preventing oil, e.g. Corn oil or soybean oil. The premix obtained in this way can then be added to the complete feed before it is fed to the animals.

The compounds according to the invention or the orally administrable agents prepared therefrom are practically ineffective in the customary in vitro test systems for determining minimal inhibitory concentrations (MIC values) of antibacterial compounds. However, they are fully effective when administered orally in vivo. example 1

Production of enrofloxacin-N-oxide

20 g of enrofloxacin were suspended with 200 ml of demineralized water. 25 ml of H ₂ O ₂ (30%) was added and the suspension was refluxed. After 3 to 4 hours, a yellow solution had formed, from which crystals precipitated on cooling. White crystals were obtained by evaporation in a crystallizing dish.

Yield: 23.6 g of crude enrofloxacin N-oxide; contains <1% enrofloxacin or other by-products (HPLC).

Example 2

20 g (55.7 mmol) of enrofloxacin are suspended in 180 ml of distilled water and 15 ml (0.147 mol) of 30% hydrogen peroxide are added. The mixture is then slowly heated to reflux. After 4 hours, the mixture was cooled to room temperature, suction filtered and dried over sulfuric acid in a desiccator.

Yield: 19.37 g (92.7%) enrofloxacin N-oxide

Content: 99.7% content of enrofloxacin <0.1%.

Example 3

2 g (5.6 mmol) of enrofloxacin are dissolved in 20 ml of chloroform, then 1.2 g (5.6 mmol) of 80% 3-chloroperbenzoic acid are added. It is stirred at room temperature until the reaction is complete. The precipitate is filtered off and dried.

Yield: 2.88 g (97%) of enrofloxacin-3-chlorobenzoate.

Example 4

2 g (5.6 mmol) of enrofloxacin are suspended in 20 ml of acetonitrile, then 0.7 ml (6.85 mmol) of 30% hydrogen peroxide are added. The The mixture is then heated to reflux. After 6 hours, the mixture is cooled and the precipitate is filtered off with suction.

Example 5

2 g (5.6 mmol) of enrofloxacin are suspended in 18 ml of saturated sodium hydrogen carbonate solution and 1.5 ml (14.7 mmol) of 30% hydrogen peroxide are added. The mixture is then heated to 50 ° C. After 90 minutes, the mixture is cooled and adjusted to pH 6 with hydrochloric acid. The resulting precipitate is stirred for two hours at room temperature, then suction filtered and dried.

Danofloxacin N-oxide

10 g (0.028 mol) of danofloxacin are suspended in 90 ml of water, 7.5 ml

(0.073 mol) 30% hydrogen peroxide was added and the mixture was heated under reflux for 3 hours. Then another 7.5 ml of 30% hydrogen peroxide are added and the mixture is heated under reflux for a further 6 hours. The mixture is then cooled, the precipitate is suction filtered, washed with water and dried over sulfuric acid in a desiccator.

Yield: 0.71 g (79.3% of theory) Purity: 95.1% (HPLC area)

For cleaning, suspend hot in 150 ml of water, let cool and suction. Yield: 7.7 g (73% of theory)

Purity: 99.5% (HPLC area) Danofloxacin content: <0.1% Melting point: 256 ° C (decomposition)

Marbofloxacin N-oxide

12.5 g (0.035 mol) of Marbofloxacin are suspended in 125 ml of saturated NaHCO ₃ solution, 9 ml (0.088 mol) of 30% hydrogen peroxide are added and the mixture is stirred at 50 ° C. for two hours. The reddish solution remains overnight at room temperature and is then adjusted to pH 6.5 with concentrated hydrochloric acid. The precipitated solid is filtered off, washed with water and dried in a desiccator over sulfuric acid. Yield: 11.71 g (88% of theory) Purity: 98.5% (HPLC area) Marbofloxacin content: <0.1% Melting point: 235 ° C (decomposition)

Ofloxacin-N-oxide

8 g (0.022 mol) ofloxacin are suspended in 80 ml of water, 5.9 ml (0.058 mol) of 30% hydrogen peroxide are added and the mixture is heated under reflux for one hour. Then leave to stand overnight. The precipitated solid is filtered off with suction, washed with a little water and dried in a desiccator over sulfuric acid.

Yield: 8.30 (quantitative) Purity: 99% (HPLC area) Ofloxacin content: <0.1% Melting point: 239 ° C (decomposition)

Example A

Calves, each weighing approximately 146 kg, were treated as follows:

a) 4 animals each received a single 5 mg / kg of a 10% aqueous solution for injection of enrofloxacin potassium salt intramuscularly. After 0.5, 1, 2, 4, 6, 8, 24 hours p.i. blood was taken from the animals and the active substance level was determined in Se m.

From 0.5 to 24 hours p.i. the fully effective dose of enrofloxacin could be detected in the semm.

b) 4 animals each received 5 mg / kg intramuscularly once of a 10% aqueous solution for injection of enrofioxacin-N-oxide potassium salt. After 0.5, 1, 2, 4, 6, 8, 24 hours p.i. blood was taken from the animals and the active ingredient level in the semm was determined.

No enrofloxacin could be detected in the semm from 0.5 to 24 hours pi (lower detection limit 0.01 μg / ml). Example B

Broilers, each weighing approximately 350 g, were treated as follows:

a) 24 animals each received 10 mg / kg of a 10% aqueous solution of enrofloxacin potassium salt once orally. After 1, 2, 4, 6, 8, 24 hours, blood was taken from the animals and the active ingredient content in

Semm determined.

From 1 to 24 hours p.a. the fully effective dose of enrofloxacin could be determined in the semm.

b) 18 animals each received 10 mg kg of a 10% aqueous solution of enrofloxacin-N-oxide orally. After 1, 2, 4, 6, 8,

Blood was taken from the animals for 24 hours and the active ingredient in the semm determined.

From 1 to 24 hours p.a. the fully effective dose of enrofloxacin could be detected in the semm.

Claims

claims

in which

X represents hydrogen, halogen, C _M - alkyl, C ^ alkoxy, NH ₂ ,

stands for = CH- or = N-.

for remains of the structures

stands in what

R ⁴ represents straight-chain or branched C 1 -C ₄ -alkyl, cyclopropyl, acyl with 1 to 3 C atoms which is optionally substituted by hydroxy or methoxy, R ^{5 represents} hydrogen, methyl, phenyl, thienyl or pyridyl,

R ^{6 represents} hydrogen or C _M alkyl,

R represents hydrogen or C _M alkyl,

R ^{8 represents} hydrogen or C alkyl, and

R ^{1 represents} an alkyl radical with 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl, 2,4-difluorophenyl or methylamino,

R represents hydrogen or alkyl having 1 to 6 carbon atoms and optionally substituted by methoxy or 2-methoxyethoxy and

Cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl,

R represents hydrogen, methyl or ethyl and

A stands for nitrogen or = CH-, = C (halogen) -, = C (OCH ₃ ) -, = C (CH ₃ ) -,

B represents oxygen, optionally substituted by methyl or phenyl = N- or = CH ₂ ,

and their pharmaceutically usable hydrates, acid addition salts and salts with bases.

Means to be administered via animal feed and drinking water

Base of

in which

X represents hydrogen, halogen, C _M alkyl, C _M alkoxy, NH ₂ ,

stands for = CH- or = N-.

for remains of the structures

stands in what

R ⁴ represents straight-chain or branched C _] -C ₄ -alkyl, cyclopropyl, acyl with 1 to 3 C atoms which is optionally substituted by hydroxy or methoxy,

R 5 represents hydrogen, methyl, phenyl, thienyl or pyridyl,

R ^{6 represents} hydrogen or C _M alkyl,

R ^{7 represents} hydrogen or C _1.4 alkyl, R ^{8 represents} hydrogen or C _M alkyl, and

R represents an alkyl radical with 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl, 2,4-difluorophenyl or methylamino,

R ^{2 represents} hydrogen or alkyl which has 1 to 6 carbon atoms and is optionally substituted by methoxy or 2-methoxyethoxy, and also cyclohexyl, benzyl,

2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl,

R »3 represents hydrogen, methyl or ethyl and

in which

Y for structural remains

stands in what

R '4 is optionally substituted by hydroxy or methoxy substitu¬ iertes straight or branched C _| -C ₄ alkyl, cyclopropyl, acyl having 1 to 3 carbon atoms,

R ^{5 represents} hydrogen, methyl, phenyl, thienyl or pyridyl,

R ^{6 represents} hydrogen or C _M alkyl,

R ^{7 represents} hydrogen or C _M - alkyl,

R ^{8 represents} hydrogen or C _M alkyl, and

R represents hydrogen or optionally methoxy-substituted alkyl having 1 to 4 carbon atoms and benzyl, 2-oxopropyl, phenacyl and ethoxycarbonylmethyl,

A stands for = N-, = CH-, = C (halogen) - or = C (OCH ₃ ) -,

4. Process for the preparation of the compounds of formula (Ia) according to

Claim 3, characterized in that one

a) the corresponding compounds (III)

in which

Y stands for the lying nitrogen-containing heterocycle belonging to the N-oxide radicals Z,

A and R ^{1 have} the meaning given in Claim 3,

reacted with oxygen released agents,

or if you

b) compounds of the formula (IV)

in which

A, R, R ^{z have} the meaning given in Claim 3 and

X is halogen, preferably fluorine or chlorine,

nitrogen-containing heterocycles of the formula (V) saturated with N-oxides

Y - H (V)

in which Y has the meaning given above,

if appropriate in the presence of acid binders.

5. Compounds of the formula (I) according to Claim 1,

in which

A stands for = CH-,

R ^{1 represents} cyclopropyl,

R ^{2 represents} hydrogen, methyl or ethyl,

for remains of the structures

stands in what

R is methyl, optionally substituted by hydroxy

Ethyl stands,

R ^{5 represents} hydrogen or methyl,

R represents hydrogen or methyl,

and their pharmaceutically usable hydrates and acid addition salts as well as the alkali, alkaline earth, silver and guanidinium salts of the related carboxylic acids.

6. Compounds of the formula (I) according to Claim 1, in which

A stands for = CH-,

R ^{1 represents} cyclopropyl,

R ^{2 represents} hydrogen, methyl or ethyl,

Y for structural remains

stands in what

R ^{4 represents} methyl, optionally substituted by hydroxy,

R ^{5 represents} hydrogen or methyl,

R represents hydrogen or methyl,

7. 4-piperazinyl-N-oxides of the active substances enrofloxacin, marbofloxacin or

Ofloxacin.

8. Use of compounds of formulas (I) or (II) according to Anspmch

1, for the production of agents against bacterial diseases which can be administered orally via drinking water or animal feed.

9. Use of compounds of the formulas (I) or (U) according to Claim 1 for the preparation of agents against bacterial diseases which can be administered orally via the feed of animals.

10. Use of compounds of the formulas (I) or (II) according to Claim 1 for combating bacterial diseases in animals when administered via the feed or the drinking water.